Oral mucositis is a common, bothersome and dose-limiting side effect of many forms of cancer chemotherapy. The lesions that result cause inflammatory and ulcerative changes that result in pain and loss of function. Consequently, patients with mucositis have difficulty eating and require pain medication. Since the frequency and severity of mucositis are related to the choice and dose of the drug being used, oncologists may shy away from optimum agents and doses in order to avoid this side effect. In addition, patients who receive myeloablative therapy are at increased risk of local and systemic infection. Since the mouth is normally rich in microorganisms, the loss of mucosal integrity which accompanies mucositis at a time when patients"" systemic defenses are compromised, results in the oral cavity being a major source of invading bacteria. In fact, the mouth is the most identifiable source of systemic bacteria in granulocytopenic cancer patients.
Patients who receive radiation therapy for tumors of the head and neck are also at high risk for oral mucositis. The frequency and severity of mucosal injury is a function of the total dose and schedule of radiation. Increasing the rate of radiation exposure results in a higher incidence of mucositis. While the current trend of using concomitant chemotherapy with radiation results in a better tumor outcome than radiation alone, these protocols are exceedingly stomatotoxic. Mucositis is often of such severity as to necessitate a break in treatment to allow the tissue to recover. Such an interruption in therapy reduces the overall anti-tumor effect of the radiation.
Historically mucositis was viewed as a process that was mediated by epithelial damage. It was believed that the non-specific toxic effects of chemotherapy or radiation resulted in DNA damage to the rapidly dividing cells of the oral basal epithelium. This resulted in cell death, atrophic changes of the mucosa, and ultimately, ulceration. However, four lines of observations suggested a biologic complexity that extended beyond an epithelial etiology. First, electron microscopic observations demonstrated that early damage was seen in both the endothelium and connective tissue underlying the epithelium and these changes preceded any noted in the epithelium. Second, administration of pleotropic cytokines which attenuated levels of the pro-inflammatory cytokines, IL-1xcex2 and TNF-xcex1, resulted in a reduction of mucositis in experimental models. Third, high levels of the same pro-inflammatory cytokines were noted in the peripheral blood of patients with non-hematologic toxicities associated with cancer chemotherapy. And fourth, alteration of the local oral environment, particularly the bacterial load and saliva, modified the course of mucositis.
I believe that cells in the endothelium, connective and basal epithelium undergo apoptosis or cell death as mucositis progresses. While there are a number of mediators which influence this outcome, I posit that the sphingolipid messenger ceramide is a major molecular driver of cell death. Of particular relevance in this patient population is the fact that ceramide may be generated in one of two ways; first, from sphingomyelin by activation of either neutral or acidic sphingomylinase; or second from dihydrosphosine following activation of ceramide synthase. TNF-xcex1, already known to play a significant role in mucositis development, actives both the acidic and neutral forms of sphingomylinase. Radiation may cause ceramide production by activation of the acidic form. Further, a number of chemotherapeutic drugs are known activators of ceramide synthase.
I propose an intervention for oral mucosal injury secondary to chemotherapy or radiation based on the inhibition of the synthesis of ceramide, blockage of its activity or by its digestion. Using a rinse and swish technique, suspensions of the drug can be used by patients immediately prior to, and continuing throughout the course of their active treatment. Topical pastes and gels can also be used. Among the possible agents are: Silymarin, a polyphenolic flavonoid derived from milk thistle, which blocks ceramide activity; 1-phenyl-2-decanoylaminon-3-morpholino-1-propanol and 1-phenyl-2-hexadecanoylaminon-3-pyrrolidino-1-propanol, both of which are inhibitors of glucosylceramide synthase; Scyphostatin, an inhibitor of neutral magnesium-dependent sphingomylinase; L-carnitine, an inhibitor of ceramide production; glutathione; and human milk bile salt-stimulated lipase, which digests ceramide.